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942
The Growing Teratoma Syndrome in a
Nongerminomatous Germ Cell Tumor
of the Pineal Gland
A Case Report and Review
Ann M. O’Callaghan, M.R.C.P.I.1
Ourania Katapodis, M.B.1
David W. Ellison, M.D.2
Jeffrey M. Theaker, M.D.2
Graham M. Mead, M.D.1
BACKGROUND. The growing teratoma syndrome is a recognized complication of
1
CRC Wessex Medical Oncology Unit, Royal
South Hants Hospital, Brintons Terrace, Southampton, United Kingdom.
2
Department of Histopathology, Southampton
University Hospitals Trust, Southampton General Hospital, Southampton, United Kingdom.
metastatic nonseminomatous germ cell tumors of the testis and is managed surgically. It may also occur in intracranial nongerminomatous germ cell tumors.
METHODS. The authors performed an English language computer search using the
EMBASE data base (from January 1980 to December 1996) for pineal tumors, read
all abstracts, and then selected all articles pertaining to germ cell tumors at this
site.
RESULTS. The case history of a 19-year-old male who presented with a pineal
nongerminomatous germ cell tumor, which was treated with chemotherapy, is
reported. Despite normalization of raised tumor marker levels, the pineal mass
enlarged during chemotherapy. This was excised and proved to be a mature teratoma. A review of the literature regarding this complication of intracranial germ
cell tumors is also presented.
CONCLUSIONS. The authors believe this to be the first reported case of growing
teratoma syndrome in the pineal gland of an adult patient, two previously reported
cases occurred in children. The authors conclude that the pineal gland is an unusual but important site in which to recognize the growing teratoma syndrome.
Cancer 1997;80:942–7. q 1997 American Cancer Society.
KEYWORDS: germ cell tumor, pineal, teratoma, yolk sac, chemotherapy, growing
teratoma syndrome.
P
Ann M. O’Callaghan, M.E.C.P.I., is supported by
the Cancer Research Campaign.
Address for reprints: Graham M. Mead, M.D.,
CRC Wessex Medical Oncology Unit, Royal
South Hants Hospital, Brintons Terrace, Southampton, SO14 OYG, United Kingdom.
Received February 19, 1997, accepted April 23,
1997.
rimary intracranial germ cell tumors are rare malignancies, representing only 1% of all intracranial neoplasms in Europe and the
U.S., but with a higher incidence in Japan, where they constitute
approximately 4% of intracranial tumors at all ages and approximately
20% in males between the ages of 10 – 25 years.1,2 These tumors arise
in the pineal or suprasellar regions (with a female preponderance
for suprasellar germinomas)3,4; histologically, they are divided into
germinomas (equivalent to gonadal seminomas and dysgerminomas)
and teratomas or nongerminomatous germ cell tumors (NGGCT).
Overall, tumors of the pineal gland are comprised of 45% germinomas,
16% NGGCT, 15% pineal parenchymal tumors, 17% gliomas, and 7%
other lipomas, cysts, metastases, and meningiomas.1
Intracranial germinomas are highly radiosensitive tumors. Recent
series have reported 10-year survival rates of 75 – 90% in patients
treated with radiotherapy alone.5,6 Similar or improved results may
be achieved with a combination of platinum-based chemotherapy
and radiotherapy.6 Like their systemic counterparts, intracranial
q 1997 American Cancer Society
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W: Cancer
Growing Teratoma Syndrome in the Pineal Gland/O’Callaghan et al.
943
FIGURE 1. (a) Magnetic resonance imaging (MRI) scan at diagnosis showing
pineal region tumor. (b) MRI scan after Week 6 of chemotherapy showing tumor
enlargement. (c) MRI scan 3 months after completion of treatment.
NGGCT respond poorly to radiotherapy7,8; with this
treatment modality, 5-year survival figures of 18 – 33%
have been reported.7,8 Platinum-containing chemotherapy used in combination with radiotherapy has
resulted in a substantial improvement in survival,9,10
with best reported results of 86% event free survival
at 4 years.9
In testicular NSGCT, chemotherapy usually results
in normalization of serum markers and complete resolution or reduction in size of metastatic masses. Residual masses are routinely resected on completion of
chemotherapy.11 In some cases enlarging tumor
masses comprising mature teratoma are observed despite disease response as judged by falling tumor
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markers. This has been termed the growing teratoma
syndrome by Logothetis et al.12
The authors report the case of a 19-year-old man
with primary pineal NGGCT who was treated with chemotherapy and developed the growing teratoma syndrome. This was successfully managed surgically.
Case Report
A 19-year-old man was admitted with a 6-month history of personality change, manifested by episodes of
aggression, and a 3-week history of persistent and increasing headaches with vomiting and intermittent
diplopia. He also had anorexia and weight loss of 5
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944
CANCER September 1, 1997 / Volume 80 / Number 5
kg. There was no relevant past medical history; his
family history included diabetes and asthma.
General examination was normal. Neurological
examination revealed some restriction of upward gaze
but was otherwise normal. However, a computed tomography (CT) scan of the brain showed a mass in
the pineal region with an adjacent calcified nodule.
CT scans of his chest and abdomen were normal, as
was testicular ultrasound. A full blood count, biochemical profile, and thyroid function tests were normal as were luteinizing hormone, follicle-stimulating
hormone, and lactate dehydrogenase levels. The human chorionic gonadotrophin-b (BHCG) level was õ
2 IU/L (normal, õ 4 IU/L) and his a-fetoprotein (AFP)
level was elevated at 32 kU/L (normal, õ 10 kU/L).
Further evaluation of the intracranial abnormality by
magnetic resonance imaging (MRI) (Fig. 1a) revealed
a heterogeneous signal intensity mass present in the
pineal region with a maximum anteroposterior dimension of just over 3.0 cm and transverse greatest dimension of 2.7 cm. The mass protruded anteriorly into the
back of the third ventricle and to the left of the midline
and had definite areas of cyst formation within it. The
anterior portion of the tectal plate was compressed by
the mass and the aqueduct of Sylvius was obstructed
with resulting moderate supratentorial hydrocephalus.
There was also mild transependymal edema. Ventriculoscopy, third ventriculostomy, and biopsy of the pineal mass were performed. Analysis of cerebrospinal
fluid (CSF ) sampled perioperatively showed elevated
tumor marker levels with BHCG at 10 IU/L and AFP
at 74 kU/L.
Histologic examination of the small specimen of
tumor revealed small strips of epithelial cells with a
high nuclear: cytoplasmic ratio set within a myxoid
stroma of elongated cells. The appearances were consistent with a diagnosis of yolk sac tumor. No elements
of mature teratoma were visualised.
Postoperative dexamethasone, 4 mg orally, every
6 hours, was prescribed and the patient was referred
to the Oncology Unit. It was decided to treat the patient with chemotherapy, according to the EpPlt/OMB
regimen as described by Smith et al.13 This is an alternating weekly schedule with etoposide, 150 mg/m2 cisplatin, 75 mg/m2 administered intravenously and
methotrexate, 12.5 mg given intrathecally on Day 1.
On Day 8, the OMB cycle commences and comprises
vincristine, 1 mg/m2 intravenously (i.v.) and methotrexate, 1 g/m2 i.v. by 24-hour infusion followed by a
48-hour infusion of bleomycin, 30 mg. Folinic acid
rescue, 15 mg orally, every 6 hours, was administered
32 hours after the start of the methotrexate infusion
and continued for 72 hours.
The serum markers were assessed weekly and CSF
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TABLE 1
Serum and Cerebrospinal Fluid Markers throughout Treatment
Serum
Presentation
Prechemotherapy
Postchemotherapy
Week 1
Week 2
Week 3
Week 4
Week 6
Postexcision
Postchemotherapy
Week 10
CSF
bHCG (IU/L)
Normal õ 4
AFP (kU/L)
Normal õ 10
bHCG
(IU/L)
AFP
(kU/L)
õ2
4
32
48
10
74
õ2
õ2
õ2
õ2
õ2
õ2
69
30
13
7
5
2
5
10
õ2
õ2
õ2
0.3
0.4
0.4
õ2
4
õ2
0.4
CSF: cerebrospinal fluid; bHCG: human chorionic gonadotropin; AFP: a-fetoprotein.
samples for analysis were obtained prior to each intrathecal injection. Serial marker results are shown in
Table 1. After surgery and the initiation of steroids and
chemotherapy, the patient’s condition improved with
reduction of his headaches. The peripheral blood and
CSF marker levels returned to normal after 4 weeks of
chemotherapy. At the end of the sixth week a routine
repeat MRI scan was performed. This scan showed an
increase in the size of the pineal mass (Fig. 1b), with
a maximum anteroposterior greatest dimension of 4
cm (compared with 3 cm previously) and a transverse
greatest dimension of 3 cm (compared with 2.7 cm
previously). The patient remained symptom free, and
there were no new abnormal physical findings.
Craniotomy was performed and the pineal tumor
was completely excised via an occipital transtentorial
approach. The maximum dimensions of the mass removed measured 30 mm 1 15 mm 1 15 mm (Fig.
2a). The entire specimen was submitted for histology,
which revealed a differentiated teratoma comprised of
mature tissues from all three germ lines (Fig. 2b). Neither high grade germ cell tumor nor necrosis was
found.
Postoperatively, Parinaud’s syndrome developed
with fixed unreactive pupils, marked downward gaze,
and disconjugate eye movements. After surgery, an
additional 4 weeks of EpPlt/OMB chemotherapy were
given. Over the ensuing 3 months, the eye movement
disorders resolved. A follow-up MRI scan, taken 3
months after the end of chemotherapy, was normal
(Fig. 1c). At last follow-up, 15 months after the completion of treatment, the patient remained in remission
and well, with normal serum markers.
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Growing Teratoma Syndrome in the Pineal Gland/O’Callaghan et al.
945
FIGURE 2. (a) Formalin fixed pineal region tumor. (b) Histology of mature teratoma showing epithelia, adipose tissue, and osteoid.
DISCUSSION
Primary intracranial germ cell tumors are rare malignancies predominantly occurring in adolescent
males.1 The etiology of these tumors is not clear. However, it is presumed that some of the primordial germ
cells, which appear in the yolk sac during the third
gestational week and migrate into the genital ridge in
the sixth week, erroneously migrate to the pineal or
suprasellar area, where they subsequently undergo
malignant change.3
Pathologically, there are two main groups of intracranial germ cell tumors: germinomas that are histologically identical to testicular seminoma, and
NGGCT, which may be comprised of any one or a
combination of the following elements: mature teratoma, embryonal carcinoma, yolk sac tumor, and choriocarcinoma.
The distinction between germinomas and NGGCT
is of paramount importance because of the divergence
in radiosensitivity between the two tumor types. Improved safety of neurosurgical biopsy techniques
means that the previous practice of empiric radiotherapy of pineal region tumors without histologic diagnosis should now be obsolete.8,14,15 Serum and CSF
marker levels are an essential adjunct to histologic
diagnosis.8
Radiotherapy is the primary treatment modality
used in germinoma, with 90% event free survival reported.9,10 Similar results are observed with a combination of chemotherapy and radiotherapy.9 This approach has the advantage of enabling a reduction of
the radiotherapy dose.9,16 – 18 The First International
Central Nervous System (CNS) Germ Cell Tumor Study
reported a complete remission rate of 82% with chemotherapy alone in patients with pure germinoma,
with patients with recurrences being salvaged with radiotherapy.19 However, given the excellent outcome
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with radiotherapy, the use of chemotherapy alone
must be confined to formal clinical trials.19
Like their systemic counterparts, NGGCT respond
poorly to radiotherapy, with 5-year survival in the region of 20 – 30% with this treatment alone.7,8 However,
the addition of cisplatin-based combination chemotherapy has improved results, with an event free survival rate of 86% at 46 months reported for cisplatin
dosages of 400 mg/m2 (in combination with radiotherapy) with inferior event free survival of 56% (median
follow-up of 65 months) observed with a lower cisplatin dose of 200 mg/m2.9 A number of platinumbased regimens have been used including the pediatric protocols MAKEI 89, in which alternating cycles of
bleomycin, etoposide, and cisplatin (BEP) and vinblastine, ifosfamide, and cisplatin are given and TC 90, in
which cycles of carboplatin and etoposide alternate
with ifosfamide and etoposide.9 The two-drug combination of cisplatin and etoposide has been favored by
some20 whereas others have used a four-drug combination of cisplatin, cyclophosphamide, vinblastine,
and bleomycin.17
The largest reported experience of the use of chemotherapy alone in patients with NGGCT is from the
First International CNS Germ Cell Tumor Study, which
included 26 patients with NGGCT who were treated
with carboplatin, etoposide, and bleomycin with high
dose cyclophosphamide given to poor responders. A
78% complete remission rate was achieved with chemotherapy (and surgery when indicated); however, 13
of these 26 patients subsequently progressed or recurred.19 Experience with EpP1t/OMB, a weekly alternating regimen that includes systemic methotrexate at
a dose of 1 g/m2, as well as alternate-week intrathecal
methotrexate as given to the patient in the current
study, has been reported in five patients.13
The role of radiotherapy in the management of
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946
CANCER September 1, 1997 / Volume 80 / Number 5
intracranial NGGCT is disputed13,19 because radiotherapy may increase the risk of toxicity without benefit.21
However, some authors strongly advocate its continuing usage22 but acknowledge this to be based on anecdotal evidence of recurrence after chemotherapy response when radiotherapy was omitted.22,23
In patients with testicular NSGCT, chemotherapy
usually results in normalization of serum markers and
complete resolution or reduction in the size of original
mass. Residual masses are routinely resected on completion of chemotherapy24 and histologic examination
may show necrosis, fibrosis, mature teratoma, or residual malignant elements.25 The growing teratoma
syndrome is a distinct clinicopathologic entity characterized by enlarging masses during or after chemotherapy in the presence of normal or falling tumor markers. Radiologic investigation often shows cystic
changes in previously identified masses and histologic
examination of resected tissue shows mature teratoma.12 It is suggested that although the malignant
elements of the tumor are responsive to chemotherapy
and reduce dramatically in size, mature teratoma is
unaffected by chemotherapy and continues to grow,
accounting for the paradoxical response to treatment.
The incidence of growing teratoma syndrome in patients with metastatic NSGCT is between 1.9 – 7.6%.12,26
It is most commonly observed at retroperitoneal disease sites, but has also been reported in the lung, supraclavicular lymph nodes, and liver.26
To the authors’ knowledge, this patient represents
the first reported case of this syndrome occurring in
a pineal germ cell tumor in an adult. The two previous
reported cases were observed in children. In the first
case, a 9-year-old girl was reported as deteriorating
neurologically after her seventh course of chemotherapy despite normalization of her tumor markers. At
postmortem examination, mature teratoma proved to
be the cause of death.13,27 Lee et al. reported a second
case in a 5-year-old Chinese boy whose neurologic
status deteriorated after his fourth cycle of BEP chemotherapy. A CT scan showed an increase in the size
of his intracranial lesion and at surgery a mature teratoma was excised.28
In the patient in the current study enlargement of
the tumor was observed on routine scan when the
patient was asymptomatic and neurologically stable.
Early detection of the growth of the mass allowed
timely semielective surgical intervention.
Because of the potential of growing teratoma in
the pineal region to cause lethal local anatomic complications, early surgical intervention is essential. Appropriate management requires a careful balance of
risks between potential growth of residual differentiated teratoma and surgical morbidity and mortality.
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Another complication of mature teratoma in situ
is the possibility of malignant change and indeed occurrence of a leiomyosarcoma in an intracranial mature teratoma has been described.29 Two cases of adenocarcinomatous transformation in an intracranial
NGGCT of the pineal region also have been reported.30
The incidence of growing teratoma syndrome in
NGGCT is impossible to estimate. Smith et al. noted
one postmortem case in a series of five patients.13 In
a recent review of the European experience of the
management of 50 of cases of NGGCT, this complication was not mentioned.9 A report from the Royal
Marsden Hospital, which included 12 cases of NGGCT,
commented that 2 patients who had responded in
terms of tumor marker evaluation had deterioration
in the radiologic appearance of the tumor. These two
cases may represent further cases of growing teratoma
syndrome at this site.7
There is some evidence that the extent of surgical
resection may influence outcome in patients with
NGGCT. Preliminary data from the First International
CNS Germ Cell Tumor Study Group trial of chemotherapy suggests that the extent of surgical resection is
a favorable prognostic factor, with gross total resection
predicting for an improved recurrence free survival.31
Sakai et al. reported 2 long term survivors who underwent total excision of their pineal tumors followed by
chemotherapy, and in their review of the characteristics of 11 long term survivors, they found that all but
2 had pineal lesions that had been almost totally removed. They suggest that aggressive extirpation of tumor followed by chemotherapy may provide more
prolonged useful survival time.32 Herrmann et al. reported successful outcomes in three children with secretory tumors who were given neoadjuvant chemotherapy with surgical resection after the first two cycles
of treatment. Further chemotherapy and radiotherapy
was administered postoperatively.22 Wider experience
of this approach was gained in the MAKEI studies, in
which 12 of 14 patients treated were alive with an
event free survival of 80% at a median follow-up of 52
months.9 In most cases, resected material was of mature histology.9,31 However, despite a similar approach
in the French TC 90 protocols, five of seven children
developed a local recurrence and died.9 In the First
International CNS Germ Cell Tumor Study secondlook surgery was strongly encouraged if less than a
complete response was achieved after the first four
cycles of chemotherapy. In six of eight patients who
were operated on either mature teratoma or necrosis
was found.19
The authors reported a case of growing teratoma
syndrome in a patient with a pineal NGGCT. To the
authors’ knowledge, this is the third such case re-
W: Cancer
Growing Teratoma Syndrome in the Pineal Gland/O’Callaghan et al.
ported. The authors reviewed the literature pertaining
to NGGCT and suggest that recognition of mature teratoma in the pineal region is important because failure
to do so has proved fatal in the past. The authors
emphasize the role of early surgical resection if possible and suggest that management of patients with
NGGCT requires a multidisciplinary approach involving the oncologist and the neurosurgeon in a similar
partnership as that existing for the management of
systemic NSGCT.
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